Pathology
Fish Model for Melanoma Fingers Culprit Mutations
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Spotlight Shines on Tag-team Gene Regulation
Oncology
Body’s Own Angiogenesis Inhibitors Check Tumor Growth
Development
Mechanical Forces Speed Up Growth of the Lung
Honors
Fund and Lectureship Honor Poussaint
Routine Screening for HIV Would Be Cost Effective
Dopamine Receptor Dances to Tune of Parkinson’s Protein
COX-2 Inhibitors May Prevent Common Surgical Complication
Carroll to Head Immunology Graduate Program
Nominations Sought for Leadership in Women’s Advancement
Nominations Invited for Biostatistics Award
Grants Available for Collaborative Research in Women’s Health
Honors and Advances
Baldwin Named New President of CBR
Lines Drawn Over Recommended Cuts in Medicare Hospital Reimbursement
Routine Screening for HIV
Would Be Cost Effective
It would make economic sense for most individuals in the United States to undergo routine testing for HIV infection. This is the conclusion of a study published in the Feb. 10 New England Journal of Medicine, by a team of researchers from HSPH, HMS, Yale, and other institutions. The senior author is HMS assistant professor of medicine Rochelle Walensky of Massachusetts General Hospital.
| “We can compare the costs and benefits of an HIV screen with treatments or diagnostics we do for other conditions.” |
“Nobody is willing to put a dollar value on a year of life,” Walensky said, “but we can compare the costs and benefits of an HIV screen with treatments or diagnostics we do for other conditions.” The team set out to determine whether routine HIV screening extends lives at a cost comparable to common interventions, like mammography or colon cancer screening.
Their model had two components. The front end, created by a group led by first author David Paltiel of Yale, simulates the acquisition of the HIV virus and the screening process, and links to a back end that simulates disease progression and treatment.
The whole HIV simulation model is a long-term project led by Kenneth Freedberg, an HSPH associate professor in the Department of Health Policy and Management, an HMS associate professor of medicine at MGH, and the director of the Program in Epidemiology and Outcomes Research at the HMS Division of AIDS.
The model results indicated that the cost of a routine HIV screen in a population with a one percent infection rate is, indeed, in line with other diagnostics that are widely deployed. Failure to screen shortens lives, because patients receive antiretroviral treatment at a later stage of the disease. Late HIV diagnosis may also increase downstream transmission.
“What this very detailed model tells us is quite simple,” said Freedberg. “When you have a relatively common disease that is fatal if untreated, and you have both effective therapies and an accurate, inexpensive test, you should be screening.”
The team has a publication in press examining how hospitals could implement a routine voluntary screen, which Walensky and Freedberg have already tested at four urgent care centers in Massachusetts. In future research, they plan to explore how patient behavior and antiretroviral therapy interact to affect the risk of transmission of HIV.
Dopamine Receptor Dances to Tune of Parkinson’s Protein
The first research paper to examine mice with a defective DJ-1 gene, which is linked to Parkinson’s disease, was published in Neuron on Feb. 17. A team led by Jie Shen of the Center for Neurologic Diseases at Brigham and Women’s Hospital created the mice and examined their behavior and the dopamine receptor function of neurons in their substantia nigra region. In Parkinson’s disease, most of the affected neurons are in the brain’s substantia nigra with axons projecting to the striatum.
No one knows the exact role of the protein product of DJ-1. Shen, an HMS associate professor of neurology, challenged her postdoctoral fellow Matthew Goldberg to engineer a mouse line with DJ-1 deleted and to identify deficits in the mice. He did so, working with collaborators from the University of Rome.
Goldberg manipulated mouse stem cells into recombining with a mutant DJ-1 form, swapping normal genes for defective ones. He merged the stem cells with normal mouse blastocysts. The resulting chimeric mice became the founders of a line with no working copy of DJ-1.
It became clear in automated monitoring experiments that these mice were less active than their normal peers in an “open field” environment. Probing thin brain slices, the researchers identified several characteristic features of the DJ-1 knockouts. In these mutants, nigral neurons quickly recovered from dopamine inhibition and resumed firing, unlike those in normal mice whose firing can be prevented by dopamine.
At the other end of the circuit, in the striatum, the researchers found a reduction in evoked dopamine. In addition, in striatal neurons, which receive dopaminergic signals from the substantia nigra, the loss of DJ-1 affected neuronal plasticity. There was a deficit in long-term depression of neuronal firing, while long-term potentiation was normal. Several of these defects could be repaired by introducing agonists that trigger D2 dopamine receptors, but not with agonists specific to D1, indicating that DJ-1’s activity is specific to D2.
Shen initially hoped to find that the mutation led to the death of specific neurons, typical of Parkinson’s disease. The mice do not yet show this nigral cell death, but Shen is pleased with the D2-related defects that were identified. “We found a middle point,” she said, referring to the chain of events that ends with nigral cell death and clinical Parkinsonism.
The aging mice may show additional changes in the substantia nigra, so Shen’s lab will continue to observe the DJ-1 knockouts. She also plans to continue working on the challenge of figuring out exactly how DJ-1 regulates D2 receptor function.
COX-2 Inhibitors May Prevent Common Surgical Complication
After surgery, bands of fibrous scar tissue often form, binding organs or tissues and sometimes causing pain, intestinal blockage, or secondary infertility. But a study by Mark Puder and colleagues suggests that the drug celecoxib (Celebrex) could prevent these adhesions from developing.
Puder, an HMS instructor in surgery, explored a chance observation from a previous study involving animals treated with celecoxib, in which experimental lesions only occasionally caused adhesions. The current investigation used a mouse model to look objectively at postsurgical adhesion prevention with nonsteroidal anti-inflammatory drugs and two COX-2 inhibitors, celecoxib and rofecoxib (Vioxx). Puder’s findings with fellow researchers at Children’s Hospital Boston were published in the Jan. 25 online Annals of Surgery.
After creating an experimental lesion and allowing it to heal, the researchers evaluated the presence and mechanical strength of adhesions that formed, identified the growth of epithelial cells with immunostaining, and quantified the growth of microvessels. There were no signs of impaired wound healing in any subjects, but there was less adhesion formation in the mice treated with COX-2 drugs, and celecoxib gave the best results. The researchers suggest that rofecoxib was somewhat less effective because it lacks celecoxib’s antifibroblastic activity.
Existing biodegradable barrier methods for minimizing adhesions may spark immune responses and infection. And unlike many agents proposed for preventing adhesions, several COX-2 inhibitors are already approved, although their status is clouded by concerns that the class raises the risk of cardiovascular problems. The one-week course of treatment required to prevent adhesions, however, is short compared to the chronic use that leads to increased risk of heart attack and stroke.
Acknowledging many pharmacodynamic differences between humans and mice, Puder is planning a multi-institutional clinical trial of celecoxib on surgical patients, in the hopes that an existing COX-2 inhibitor may soon help patients recover more fully from many kinds of surgery.